KEY TAKEAWAYS
- The PIONeeR phase 2 trial aimed to investigate targeting 4 resistance pathways to improve outcomes in advanced NSCLC after anti-PD-(L)1 therapy.
- The primary endpoint was to determine DCR.
- Researchers noted prolonged responses in some patients, indicating the promise of durvalumab combinations despite no arm surpassing docetaxel.
Anti-PD-(L)1 therapies are approved for treating advanced non-small cell lung cancer (NSCLC), but many patients progress during treatment, leaving few options available post-therapy.
In this PIONeeR trial, Michiel S. Van der Heijden and the team aimed to address this issue by targeting four major resistance pathways to overcome anti-PD-(L)1 resistance.
They performed an inclusive analysis in this open-label, multicenter, controlled randomized study utilizing a Bayesian adaptive design. Advanced patients with NSCLC having disease progression after sequential or concomitant PD-(L)1 and platinum-based chemotherapy were eligible for participation.
Patients were randomly assigned to 1 of 5 arms: Arm A received Durvalumab + Monalizumab, Arm B received Du + Oleclumab, Arm C received Du + Ceralasertib, Arm D (control) received Docetaxel, and Arm E received Du + Savolitinib.
The primary endpoint was the 12-week Disease Control Rate (12-w DCR) assessed by RECIST1.1. Key secondary endpoints included Duration of Response (DoR), Overall Response Rate (ORR), Progression-Free Survival (PFS), overall survival (OS), and safety. Interim analyses applied a futility boundary of 30%, with a combination arm considered effective if there was a high probability (P ≥ 90%) for the 12-w DCR to exceed that of Arm D.
About 114 patients with NSCLC were randomized across the trial arms: A, n=28; B, n=3; C, n=32; D, n=31; and E, n=20. Arms B and E were prematurely closed due to a lack of efficacy. Of these 11 patients in arm D withdrew prior to treatment. The 12-w DCR was 54.5% (95% CI [34.0%; 74.3%]) in the control arm compared to 24.1% [10.7%; 41.0%] in arm A, 0% in arm B, 50% [33.1%; 66.9%] in arm C, and 13.6% [3.0%; 30.4%] in arm E; P values were 1.2% and 36.8% for arms A and C, respectively.
No significant improvements in PFS or OS were observed in the experimental arms compared to arm D. However, 5 patients achieved a partial response (PR) by RECIST in arm C, with a median DoR of 5.6 months [2.1; 9.7]. No unexpected safety signals were reported. Preliminary biomarker analyses will be presented during the meeting.
The study concluded that while no experimental arm exceeded the outcomes of docetaxel, the presence of long DoR in some patients with NSCLC indicates that durvalumab combinations may be highly effective. Ongoing biomarker research aims to identify patients who are most likely to benefit from these combination treatments.
The trial was sponsored by the Assistance Publique Hopitaux De Marseille.
Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/240
Clinical Trial: https://clinicaltrials.gov/study/NCT03833440
Tomasini P, Cropet C, Jeanson A, et al. (2024). “Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients with PD-(L)1 inhibitors resistance (PIONeeR): A phase Ib/IIa clinical trial targeting identified resistance pathways.” Presented at ESMO 2024 (Abstract LBA8).
